RNA Splicing Errors Drive Aging — and Could Be the Next Therapeutic Target

Why do our tissues deteriorate with age even when our DNA remains largely intact? A compelling new review argues that a major culprit is the progressive breakdown of RNA splicing — the essential molecular editing process that converts raw genetic transcripts into functional proteins. When splicing goes wrong, cells produce aberrant proteins or trigger stress responses that erode tissue integrity over decades.

The review, published in Trends in Molecular Medicine, synthesizes mechanistic biology, stem-cell science, and longevity research to propose a unifying concept: the 'splicing axis of aging.' The authors document how aging transcriptomes show widespread RNA processing dysfunction, including increased intron retention (where sections of RNA that should be discarded remain in the final transcript), cryptic splice-site usage, and failures in RNA quality control. These disruptions arise from somatic mutations as well as accumulated transcriptional, metabolic, and proteostatic stress — all hallmarks already recognized in aging biology.

Critically, the review highlights that the same splicing abnormalities seen in normal aging also appear in major age-associated diseases. Clonal hematopoiesis — the age-related expansion of mutant blood stem-cell clones that raises cardiovascular and leukemia risk — and neurodegenerative diseases both show overlapping splicing defects. This convergence suggests that correcting RNA processing errors could simultaneously address multiple age-related conditions.

From a therapeutic standpoint, the authors outline emerging strategies aimed at restoring spliceosome integrity and RNA homeostasis. While specific compounds are not detailed in the abstract, the framework points toward small molecules, RNA-based therapies, and proteostasis interventions as promising directions.

The implications for regenerative medicine and longevity science are significant. If declining RNA-processing fidelity is indeed a unifying contributor to aging across tissues and systems, it elevates RNA splicing to the status of a targetable hallmark — one that could be addressed pharmacologically to extend healthspan. This summary is based on the abstract only, as the full text is not open access.